Melatonin as an adjuvant: reshaping glaucoma treatment strategies

Glaucoma continues to be a challenging condition to manage due to its complex nature and significant impact on patients’ lives. Characterized by distinct features such as optic disc cupping, visual field loss, and ganglion cell complex thinning, understanding the mechanisms behind these changes, and other related sequelae remains an area of ongoing research. Of interest, the relationship between circadian and sleep disturbances and glaucoma are unfolding as a topic deserving of more attention. While prior studies suggested the association between glaucoma and obstructive sleep apnoea, the effect of the circadian dysfunction in glaucoma patients has not been extensively investigated. The circadian system impacts various functions including mood, cognition, and metabolism. Circadian misalignment can lead to a reduction in the quality of sleep as well as metabolic changes, such as reduced insulin sensitivity and a cytokine shift towards an inflammatory state [1]. New evidence has suggested that melatonin, a hormone involved in the regulation of circadian function, has been associated with a reduced risk of age-related macular degeneration development or progression [2]. Of interest, disturbances in sleep could also negatively affect nocturnal intraocular pressure (IOP) regulation, resulting in worsening glaucoma through the dysregulation of IOP and increased neuroinflammation [3–5]. The interaction of glaucoma, sleep, and circadian alignment may provide new avenues for treatment for glaucoma through IOP regulation, reducing inflammation, and improving patients’ quality of life.

Recent investigations demonstrated sleep disturbance and reduced melatonin production in patients with glaucoma. Table 1 summarizes findings from previous studies investigating the relationship between glaucoma and sleep. Gao and colleagues showed that patients with advanced glaucoma suffered from sleep disturbances (e.g., insufficient duration and/or poor quality), possibly related to the loss of retinal ganglion cells (RGC) [3]. Specifically, intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subclass of the RGC that contain the photopigment melanopsin. These cells project to various areas of the brain to execute various non-vision forming functions such synchronization of circadian rhythms, form the pupillary light reflex, and light induced suppression of melatonin biosynthesis [3]. Indeed, glaucoma patients demonstrated decreasing nocturnal urinary 6-sulfatoxymelatonin, a major melatonin metabolite, with increasing glaucoma severity [6, 7]. The deterioration of sleep quality and melatonin production exceeded typical age-related decline and worsened in individuals with severe glaucoma.

Table 1.

Previous studies investigating the relationship between glaucoma and sleep disturbances.

Study Reference	Design	Sample Size	Outcome of Interest	Specific Results	Brief Summary
Wang et al., [11]	Cross-sectional	92 POAG 48 PACG 99 Control	Sleep disturbances assessed using Pittsburgh Quality Sleep Index	Prevalence of sleep disturbances was higher in patients with PACG than in controls in age groups 41–60 and 61–80 (X2-test, P < 0.05), higher in patients with PACG compared to POAG in age group 61–80 (X2-test, P < 0.05)	The prevalence of sleep disturbances in patients with PACG and POAG is higher than controls measured by the Pittsburgh Quality Sleep Index
Gracitelli et al., [12]	Cross-sectional	32 POAG 13 Control	ipRGC activity measured by post-illumination pupillary response and sleep quality as measured by polysomnography	A statistically significant correlation was observed between mean RNFL thickness and peak and sustained responses to blue flash. An inverse correlation between peak response to blue flash and average REM latency was observed (P = 0.004)	Glaucoma related impairment in ipRGCs leads to alterations in pupillary response and sleep quality as observed by polysomnography.
Kim et al., [6]	Non-randomized Prospective	41 POAG 44 Control	Urine melatonin changes in patients with POAG (low tension pretreatment IOP < 21 vs high tension pretreatment IOP > 21)	AMT6/creatinine level in high tension glaucoma (19.74 ± 3.12 ng/mg) was significantly lower than that of the control group (30.35 ± 3.05 ng/mg) (P = 0.0014)	A significant difference was observed in urinary melatonin excretion between high tension glaucoma group and controls.
Yoshikawa et al., [7]	Cross-sectional	118 Glaucoma 395 Control	Urine melatonin measurement based on glaucoma severity as measured by visual field mean deviation and retinal nerve fiber layer thickness.	The log transformed urine melatonin excretion (UME) was lower in glaucoma patients (3.05 log ng/mg) compared to controls (3.24 log ng/mg) (P = 0.010)	Patients with glaucoma had lower urinary melatonin compared to controls. Patients with structurally and functionally severe glaucoma had significantly lower urinary melatonin.
Gubin et al., [10]	Prospective	65 Stable POAG 50 Advanced POAG	Circadian rhythm as observed by body temperature, retinal ganglion cell function, intra-ocular pressure, sleep quality, and mood before and after melatonin use.	Melatonin induced circadian phase advancement of body temperature in Stable-POAG and Advanced-POAG groups (P < 0.0001). Decrease in IOP depended upon initial 24 h mean before treatment and decreased to a greater extent in individuals with a higher IOP. After melatonin supplementation PSQI scores of sleep latency, efficiency, duration, and quality improved significantly.	Melatonin use was correlated with greater IOP control, RGC function, and circadian alignment as measured by body temperature. Self-reported sleep quality and mood were also improved with a greater effect in patients with advanced glaucoma
Jimura et al., [8]	Cross-sectional	138 Glaucoma Eyes	ipRGC function through post-illumination pupillary response (PIPR) as associated with sleep disturbances measured by actigraphy	In the severe glaucoma group with lowest tertile ipRGC function demonstrated significantly shorter total sleep time, lower sleep efficiency, and longer wake after sleep onset than did the highest tertile group according to net PIPR change (P = 0.009, P = 0.027, and P = 0.035, respectively)	A significant association between impaired ipRGC function and decreased sleep quality in patients with severe glaucoma.

POAG primary open-angle glaucoma, PACG primary angle closure glaucoma, RNFL retinal nerve fibre layer, aMT6 nocturnal urinary excretion of 6-sulfatoxymelatonin, ipRGC intrinsically photosensitive retinal ganglion cells.

As melatonin plays a significant role in circadian and sleep functioning, the loss of ipRGC in glaucoma could disrupt circadian rhythms and sleep patterns, potentially creating a vicious cycle wherein poor sleep worsens glaucoma while the progression of glaucoma further disrupts sleep and circadian rhythm (Fig. 1) [3]. It is expected that with ipRGC loss there would be a diminished pupillary light response (PLR), which is supported in murine models with 50% ipRGC loss [3]. The change in the PLR is greater after blue light stimulation compared to red, which is consistent with the blue light sensitivity of melanopsin produced by ipRGCs. A difference in the PLR was observed when comparing early and advanced glaucoma patients. This concept is further supported by a recent study by Jimura and colleagues which quantified the ipRGC dysfunction via a diminished post-illumination pupil response in glaucoma patients with objective sleep disturbances. A significant association was observed between the ipRGC dysfunction in severe glaucoma and reduced objective measures of sleep efficiency, sleep duration, and self-reported sleep quality [8].

Fig. 1. Pathophysiology of glaucoma-related sleep and circadian disturbances.

Effect of glaucomatous damage on intrinsically photosensitive retinal ganglion cells and subsequent changes in sleep and circadian function.

The intriguing question therefore arises if exogenous melatonin could help optimize sleep and circadian regulation in glaucoma patients. The circadian rhythm of IOP is inversely related to melatonin levels with the highest levels occurring at night. Specific melatonin receptors (MT1 and MT2) are found in various ocular structures, and potentially play a role in IOP regulation through modulation of aqueous humour dynamics [9]. While the main synthesis occurs in the pineal gland, melatonin synthesis also occurs in the retina, the lens, and iris and ciliary body of the eye. The presence of melatonin in the ciliary body may play a crucial role in IOP homeostasis by interacting with adrenergic/melatonin receptor complexes in ciliary process and being involved in receptor-receptor interactions [9]. Gubin and colleagues explored the effects of melatonin supplements by administering 2 mg slow-release melatonin prior to sleep to patients with glaucoma for 90 days. Subjectively, the patients reported improved self-reported sleep quality, and decreased depressive symptoms. Melatonin also led to circadian phase advancement as measured by body temperature (Tb) across all patients, and an increase in Tb amplitude with a lesser effect in patients with advanced primary open angle glaucoma (POAG) [10]. Interestingly, they also found that melatonin not only lowered the IOP relative to the initial 24 h mean IOP, but also reduced the diurnal IOP fluctuation [10]. The effects were to a greater extent in those with a higher IOP and those with advanced POAG respectively. Lastly, they observed changes in pattern electroretinograms waveforms that were suggestive of protective/restorative effects on RGCs following melatonin use [10]. Although these results are promising, the lack of randomization warrants further investigation.

In conclusion, glaucoma presents a challenging journey where progress often means either worsening vision, or enduring uncomfortable, seemingly unrewarding treatments. Furthermore, sleep disturbances can lead to depressed mood, cognitive dysfunction, inflammation and IOP dysregulation leading to worsening disease, leading to a relentless cycle. Melatonin is a potential therapeutic option, which can simultaneously improve IOP control, sleep/circadian functioning, and quality of life. Longitudinal studies are needed to explore the mechanisms of their overall effects on IOP and sleep/circadian functioning over time. In addition to melatonin, there are opportunities to optimize sleep through behavioural and environmental modifications. Notably, over-the-counter melatonin supplements are classified as dietary supplements, which are not subject to the same regulations as medications. Thus, further studies regarding the optimal dosage, and long-term efficacy and safety of melatonin use in glaucoma are warranted. While traditional management, such as medical, laser and surgical interventions are crucial for IOP management, integrating methods that enhance daily living can profoundly uplift patients, underscoring the multifaceted nature of effective glaucoma care. Given its accessibility and potential benefits, melatonin presents as an encouraging adjunctive treatment warranting further attention and investigation.

Author contributions

MA: Literature review and manuscript writing. SR: Manuscript editing and review. TSV: Manuscript editing and review.

Funding

Illinois Society for the Prevention of Blindness and NIH P30 EY007192, Unrestricted Departmental Grant from Research to Prevent Blindness. Grant Number R01EY029782 from National Eye Institute.

Competing interests

SR has received speaker fee from Eli Lily. The other authors declare no competing interests.